tbuckley/cabot-search huggingface dataset:
Prophylactic terlipressin infusion for severe postreperfusion syndrome in patients undergoing deceased donor liver transplantation. The TIPS-DDLT randomized controlled trial
Authors: Liang Zhang, Ming Tian, Li-Ying Sun, Zhi-Jun Zhu
Journal: International Journal of Surgery (2023)

Severe postreperfusion syndrome (PRS) is a critical and potentially catastrophic event during deceased donor liver transplantation (LT). Terlipressin has been widely used as a renoprotective agent during the perioperative period of LT. This study was designed to evaluate whether prophylactic terlipressin would reduce the occurrence of severe PRS in deceased donor LT.In this single-center, randomized, double-blind trial, we randomly assigned adults who underwent deceased donor LT to receive 1 mg of terlipressin or placebo immediately after portal vein (PV) clamping. The primary outcome was the incidence of severe PRS after PV declamping, defined according to hypotension-based criteria per the Peking criteria.Between March 2019 and January 2021, we enrolled 64 patients and randomly assigned 32 to the terlipressin group and 32 to the control group. Severe PRS was significantly less frequent in the terlipressin group than in the control group (9.4 vs. 53.1%; OR, 0.09; 95% CI, 0.02-0.36; P <0.001). The vasopressor requirements for inferior vena cava clamping and severe PRS were significantly reduced by the intervention compared to controls (all P <0.01). Prophylactic terlipressin stabilized the mean arterial pressure ( P =0.001) and heart rate ( P =0.040) at 30 min after anhepatic phase but increased the pulmonary capillary wedge pressure (PCWP) at 5 min after reperfusion ( P =0.003). Patients in the terlipressin group had a decreased right PV flow velocity following reperfusion ( P =0.001), a longer postoperative mechanical ventilation time ( P =0.029), a lower initial poor graft function rate ( P =0.012), and lower peak alanine transaminase levels ( P =0.032) after transplantation.The prophylactic use of terlipressin reduces the incidence of severe PRS in deceased donor LT. However, concerns remain regarding elevated PCWP.
Case 14-2023: A 31-Year-Old Man with Redness of the Right Eye
Authors: Miriam B. Barshak, Caitlin M. Dugdale, Roberto Pineda
Journal: New England Journal of Medicine (2023)

A 31-year-old man was evaluated because of redness and pain of the right eye. He was taking tecovirimat for mpox, which had been diagnosed 2 days earlier. A diagnosis was made.
Can ChatGPT/GPT-4 assist surgeons in confronting patients with Mpox and handling future epidemics?
Authors: Yongbin He, Haiyang Wu, Yan Chen, Dewei Wang, Weiming Tang, M. Anthony Moody, Guoxin Ni, Shuqin Gu
Journal: International Journal of Surgery (2023)

He, Yongbin; Wu, Haiyang; Chen, Yan; Wang, Dewei; Tang, Weiming; Moody, M. Anthony; Ni, Guoxin; Gu, Shuqin Author Information
Evolutionary psychiatry: foundations, progress and challenges
Authors: Randolph M. Nesse
Journal: World Psychiatry (2023)

Evolutionary biology provides a crucial foundation for medicine and behavioral science that has been missing from psychiatry. Its absence helps to explain slow progress; its advent promises major advances. Instead of offering a new kind of treatment, evolutionary psychiatry provides a scientific foundation useful for all kinds of treatment. It expands the search for causes from mechanistic explanations for disease in some individuals to evolutionary explanations for traits that make all members of a species vulnerable to disease. For instance, capacities for symptoms such as pain, cough, anxiety and low mood are universal because they are useful in certain situations. Failing to recognize the utility of anxiety and low mood is at the root of many problems in psychiatry. Determining if an emotion is normal and if it is useful requires understanding an individual's life situation. Conducting a review of social systems, parallel to the review of systems in the rest of medicine, can help achieve that understanding. Coping with substance abuse is advanced by acknowledging how substances available in modern environments hijack chemically mediated learning mechanisms. Understanding why eating spirals out of control in modern environments is aided by recognizing the motivations for caloric restriction and how it arouses famine protection mechanisms that induce binge eating. Finally, explaining the persistence of alleles that cause serious mental disorders requires evolutionary explanations of why some systems are intrinsically vulnerable to failure. The thrill of finding functions for apparent diseases is evolutionary psychiatry's greatest strength and weakness. Recognizing bad feelings as evolved adaptations corrects psychiatry's pervasive mistake of viewing all symptoms as if they were disease manifestations. However, viewing diseases such as panic disorder, melancholia and schizophrenia as if they are adaptations is an equally serious mistake in evolutionary psychiatry. Progress will come from framing and testing specific hypotheses about why natural selection left us vulnerable to mental disorders. The efforts of many people over many years will be needed before we will know if evolutionary biology can provide a new paradigm for understanding and treating mental disorders.
Candidate biomarkers in psychiatric disorders: state of the field
Authors: Anissa Abi‐Dargham, Scott J. Moeller, Farzana Ali, Christine DeLorenzo, Katharina Domschke, Guillermo Horga, Amandeep Jutla, Roman Kotov, Martin P. Paulus, Jose M. Rubio, Gerard Sanacora, Jeremy Veenstra‐VanderWeele, John H. Krystal
Journal: World Psychiatry (2023)

The field of psychiatry is hampered by a lack of robust, reliable and valid biomarkers that can aid in objectively diagnosing patients and providing individualized treatment recommendations. Here we review and critically evaluate the evidence for the most promising biomarkers in the psychiatric neuroscience literature for autism spectrum disorder, schizophrenia, anxiety disorders and post‐traumatic stress disorder, major depression and bipolar disorder, and substance use disorders. Candidate biomarkers reviewed include various neuroimaging, genetic, molecular and peripheral assays, for the purposes of determining susceptibility or presence of illness, and predicting treatment response or safety. This review highlights a critical gap in the biomarker validation process. An enormous societal investment over the past 50 years has identified numerous candidate biomarkers. However, to date, the overwhelming majority of these measures have not been proven sufficiently reliable, valid and useful to be adopted clinically. It is time to consider whether strategic investments might break this impasse, focusing on a limited number of promising candidates to advance through a process of definitive testing for a specific indication. Some promising candidates for definitive testing include the N170 signal, an event‐related brain potential measured using electroencephalography, for subgroup identification within autism spectrum disorder; striatal resting‐state functional magnetic resonance imaging (fMRI) measures, such as the striatal connectivity index (SCI) and the functional striatal abnormalities (FSA) index, for prediction of treatment response in schizophrenia; error‐related negativity (ERN), an electrophysiological index, for prediction of first onset of generalized anxiety disorder, and resting‐state and structural brain connectomic measures for prediction of treatment response in social anxiety disorder. Alternate forms of classification may be useful for conceptualizing and testing potential biomarkers. Collaborative efforts allowing the inclusion of biosystems beyond genetics and neuroimaging are needed, and online remote acquisition of selected measures in a naturalistic setting using mobile health tools may significantly advance the field. Setting specific benchmarks for well‐defined target application, along with development of appropriate funding and partnership mechanisms, would also be crucial. Finally, it should never be forgotten that, for a biomarker to be actionable, it will need to be clinically predictive at the individual level and viable in clinical settings.
Pediatric Adrenocortical Neoplasms: A Study Comparing Three Histopathological Scoring Systems
Authors: Hemlata Jangir, Isheeta Ahuja, Shipra Agarwal, Vishesh Jain, Jagdish Prasad Meena, Sandeep Agarwala, Rajni Sharma, Mehar Chand Sharma, Venkateswaran K. Iyer, Kalaivani Mani
Journal: Endocrine Pathology (2023)
High Targeting Specificity toward Pulmonary Inflammation Using Mesenchymal Stem Cell‐Hybrid Nanovehicle for an Efficient Inflammation Intervention
Authors: Yuanqin Su, Ting Huang, Hao Sun, Ruyi Lin, Xixi Zheng, Qiong Bian, Jinsong Zhang, Shihan Chen, Honghui Wu, Donghang Xu, Tianyuan Zhang, Jianqing Gao
Journal: Advanced Healthcare Materials (2023)

Abstract Pulmonary inflammation is one of the most reported tissue inflammations in clinic. Successful suppression of inflammation is vital to prevent further inevitably fatal lung degeneration. Glucocorticoid hormone, such as methylprednisolone (MP), is the most applied strategy to control the inflammatory progression yet faces the challenge of systemic side effects caused by the requirement of large‐dosage and frequent administration. Highly efficient delivery of MP specifically targeted to inflammatory lung sites may overcome this challenge. Therefore, the present study develops an inflammation‐targeted biomimetic nanovehicle, which hybridizes the cell membrane of mesenchymal stem cell with liposome, named as MSCsome. This hybrid nanovehicle shows the ability of high targeting specificity toward inflamed lung cells, due to both the good lung endothelium penetration and the high uptake by inflamed lung cells. Consequently, a single‐dose administration of this MP‐loaded hybrid nanovehicle achieves a prominent treatment of lipopolysaccharide‐induced lung inflammation, and negligible treatment‐induced side effects are observed. The present study provides a powerful inflammation‐targeted nanovehicle using biomimetic strategy to solve the current challenges of targeted inflammation intervention.
Metachronous lesions after gastric endoscopic submucosal dissection: first assessment of the FAMISH prediction score
Authors: Andreia Rei, Raquel Ortigão, Mariana Pais, Luís P. Afonso, Pedro Pimentel-Nunes, Mário Dinis-Ribeiro, Diogo Libânio
Journal: Endoscopy (2023)

Background Surveillance after gastric endoscopic submucosal dissection (ESD) is recommended for all patients owing to the persistent risk of metachronous gastric lesions (MGLs). We developed and validated a prediction score to estimate MGL risk after ESD for early neoplastic gastric lesions, to define an individualized and cost-saving approach. Methods Clinical predictors and a risk score were derived from meta-analysis data. A retrospective, single-center, cohort study including patients with ≥ 3 years of standardized surveillance after ESD was conducted for score validation. Predictive accuracy of the score by the area under the receiver operating characteristic curve (AUC) was assessed and cumulative probabilities of MGL were estimated. Results The risk score (0–9 points) included six clinical predictors (scored 0–3): positive family history of gastric cancer, older age, male sex, corpus intestinal metaplasia, synchronous gastric lesions, and persistent Helicobacter pylori infection (FAMISH). The study population included 263 patients. The MGL rate was 16 %. The score diagnostic accuracy for predicting MGL at 3 years’ follow-up, measured by the AUC, was 0.704 (95 %CI 0.603–0.806). At 3 years and a cutoff &lt; 2, the score achieved maximal sensitivity and negative predictive value; 15 % of patients could be assigned to a low-risk group, in which the progression to MGL was significantly lower than for the high-risk group (P = 0.04). Conclusion The FAMISH score might be a useful tool to accurately identify patients with low-to-intermediate risk for MGL at 3 years of follow-up who could have surveillance intervals extended to reduce the burden of care.
Inhibition of p38α MAPK restores neuronal p38γ MAPK and ameliorates synaptic degeneration in a mouse model of DLB/PD
Authors: Michiyo Iba, Changyoun Kim, Somin Kwon, Marcell Szabo, Liam Horan-Portelance, Cody J. Peer, William D. Figg, Xylena Reed, Jinhui Ding, Seung-Jae Lee, Robert A. Rissman, Mark R. Cookson, Cassia Overk, Wolf Wrasidlo, Eliezer Masliah
Journal: Science Translational Medicine (2023)

Alterations in the p38 mitogen-activated protein kinases (MAPKs) play an important role in the pathogenesis of dementia with Lewy bodies (DLB) and Parkinson's disease (PD). Activation of the p38α MAPK isoform and mislocalization of the p38γ MAPK isoform are associated with neuroinflammation and synaptic degeneration in DLB and PD. Therefore, we hypothesized that p38α might be associated with neuronal p38γ distribution and synaptic dysfunction in these diseases. To test this hypothesis, we treated in vitro cellular and in vivo mouse models of DLB/PD with SKF-86002, a compound that attenuates inflammation by inhibiting p38α/β, and then investigated the effects of this compound on p38γ and neurodegenerative pathology. We found that inhibition of p38α reduced neuroinflammation and ameliorated synaptic, neurodegenerative, and motor behavioral deficits in transgenic mice overexpressing human α-synuclein. Moreover, treatment with SKF-86002 promoted the redistribution of p38γ to synapses and reduced the accumulation of α-synuclein in mice overexpressing human α-synuclein. Supporting the potential value of targeting p38 in DLB/PD, we found that SKF-86002 promoted the redistribution of p38γ in neurons differentiated from iPS cells derived from patients with familial PD (carrying the A53T α-synuclein mutation) and healthy controls. Treatment with SKF-86002 ameliorated α-synuclein-induced neurodegeneration in these neurons only when microglia were pretreated with this compound. However, direct treatment of neurons with SKF-86002 did not affect α-synuclein-induced neurotoxicity, suggesting that SKF-86002 treatment inhibits α-synuclein-induced neurotoxicity mediated by microglia. These findings provide a mechanistic connection between p38α and p38γ as well as a rationale for targeting this pathway in DLB/PD.
A first-in-human study of the fibroblast activation protein–targeted, 4-1BB agonist RO7122290 in patients with advanced solid tumors
Authors: Ignacio Melero, Tamara Tanos, Mariana Bustamante, Miguel F. Sanmamed, Emiliano Calvo, Irene Moreno, Victor Moreno, Tatiana Hernandez, Maria Martinez Garcia, Alejo Rodriguez-Vida, Josep Tabernero, Analia Azaro, Mariano Ponz-Sarvisé, Iben Spanggaard, Kristoffer Rohrberg, Ernesto Guarin, Eveline Nüesch, Iakov I. Davydov, Chiahuey Ooi, José Duarte, Evelyne Chesne, Christine McIntyre, Maurizio Ceppi, Marta Cañamero, Oliver Krieter
Journal: Science Translational Medicine (2023)

This first-in-human study evaluated RO7122290, a bispecific fusion protein carrying a split trimeric 4-1BB (CD137) ligand and a fibroblast activation protein α (FAP) binding site that costimulates T cells for improved tumor cell killing in FAP-expressing tumors. Patients with advanced or metastatic solid tumors received escalating weekly intravenous doses of RO7122290 as a single agent ( n = 65) or in combination with a 1200-milligram fixed dose of the anti–programmed death-ligand 1 (anti–PD-L1) antibody atezolizumab given every 3 weeks ( n = 50), across a tested RO7122290 dose range of 5 to 2000 milligrams and 45 to 2000 milligrams, respectively. Three dose-limiting toxicities were reported, two at different RO7122290 single-agent doses (grade 3 febrile neutropenia and grade 3 cytokine release syndrome) and one for the combination (grade 3 pneumonitis). No maximum tolerated dose was identified. The pharmacokinetic profile of RO7122290 suggested nonlinearity in elimination. The observed changes in peripheral and tissue pharmacodynamic (PD) biomarkers were consistent with the postulated mechanism of action. Treatment-induced PD changes included an increase in proliferating and activated T cells in peripheral blood both in the single-agent and combination arms. Increased infiltration of intratumoral CD8 + and Ki67 + CD8 + T cells was observed for both treatment regimens, accompanied by the up-regulation of T cell activation genes and gene signatures. Eleven patients experienced a complete or partial response, six of whom were confirmed to be immune checkpoint inhibitor naive. These results support further evaluation of RO7122290 in combination with atezolizumab or other immune-oncology agents for the treatment of solid tumors.
Autologous neutralizing antibodies increase with early antiretroviral therapy and shape HIV rebound after treatment interruption
Authors: Elmira Esmaeilzadeh, Behzad Etemad, Christy L. Lavine, Lauren Garneau, Yijia Li, James Regan, Colline Wong, Radwa Sharaf, Elizabeth Connick, Paul Volberding, Manish Sagar, Michael S. Seaman, Jonathan Z. Li
Journal: Science Translational Medicine (2023)

Early initiation of antiretroviral therapy (ART) alters viral rebound kinetics after analytic treatment interruption (ATI) and may play a role in promoting HIV-1 remission. Autologous neutralizing antibodies (aNAbs) represent a key adaptive immune response in people living with HIV-1. We aimed to investigate the role of aNAbs in shaping post-ATI HIV-1 rebound variants. We performed single-genome amplification of HIV-1 env from pre-ART and post-ATI plasma samples of 12 individuals who initiated ART early after infection. aNAb activity was quantified using pseudoviruses derived from the most common plasma variant, and the serum dilution that inhibited 50% of viral infections was determined. aNAb responses matured while participants were on suppressive ART, because on-ART plasma and purified immunoglobulin G (IgG) demonstrated improved neutralizing activity against pre-ART HIV-1 strains when compared with pre-ART plasma or purified IgG. Post-ATI aNAb responses exerted selective pressure on the rebounding viruses, because the post-ATI HIV-1 strains were more resistant to post-ATI plasma neutralization compared with the pre-ART virus. Several pre-ATI features distinguished post-treatment controllers from noncontrollers, including an infecting HIV-1 sequence that was more similar to consensus HIV-1 subtype B, more restricted proviral diversity, and a stronger aNAb response. Post-treatment control was also associated with the evolution of distinct N-glycosylation profiles in the HIV-1 envelope. In summary, aNAb responses appeared to mature after early initiation of ART and applied selective pressure on rebounding viruses. The combination of aNAb activity with select HIV-1 sequence and reservoir features identified individuals with a greater chance of post-treatment control.
Broadly neutralizing antibodies against sarbecoviruses generated by immunization of macaques with an AS03-adjuvanted COVID-19 vaccine
Authors: Yupeng Feng, Meng Yuan, John M. Powers, Mengyun Hu, Jennifer E. Munt, Prabhu S. Arunachalam, Sarah R. Leist, Lorenza Bellusci, JungHyun Kim, Kaitlin R. Sprouse, Lily E. Adams, Sumana Sundaramurthy, Xueyong Zhu, Lisa M. Shirreff, Michael L. Mallory, Trevor D. Scobey, Alberto Moreno, Derek T. O’Hagan, Harry Kleanthous, Francois J. Villinger, David Veesler, Neil P. King, Mehul S. Suthar, Surender Khurana, Ralph S. Baric, Ian A. Wilson, Bali Pulendran
Journal: Science Translational Medicine (2023)

The rapid emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants that evade immunity elicited by vaccination has placed an imperative on the development of countermeasures that provide broad protection against SARS-CoV-2 and related sarbecoviruses. Here, we identified extremely potent monoclonal antibodies (mAbs) that neutralized multiple sarbecoviruses from macaques vaccinated with AS03-adjuvanted monovalent subunit vaccines. Longitudinal analysis revealed progressive accumulation of somatic mutation in the immunoglobulin genes of antigen-specific memory B cells (MBCs) for at least 1 year after primary vaccination. Antibodies generated from these antigen-specific MBCs at 5 to 12 months after vaccination displayed greater potency and breadth relative to those identified at 1.4 months. Fifteen of the 338 (about 4.4%) antibodies isolated at 1.4 to 6 months after the primary vaccination showed potency against SARS-CoV-2 BA.1, despite the absence of serum BA.1 neutralization. 25F9 and 20A7 neutralized authentic clade 1 sarbecoviruses (SARS-CoV, WIV-1, SHC014, SARS-CoV-2 D614G, BA.1, and Pangolin-GD) and vesicular stomatitis virus–pseudotyped clade 3 sarbecoviruses (BtKY72 and PRD-0038). 20A7 and 27A12 showed potent neutralization against all SARS-CoV-2 variants and multiple Omicron sublineages, including BA.1, BA.2, BA.3, BA.4/5, BQ.1, BQ.1.1, and XBB. Crystallography studies revealed the molecular basis of broad and potent neutralization through targeting conserved sites within the RBD. Prophylactic protection of 25F9, 20A7, and 27A12 was confirmed in mice, and administration of 25F9 particularly provided complete protection against SARS-CoV-2, BA.1, SARS-CoV, and SHC014 challenge. These data underscore the extremely potent and broad activity of these mAbs against sarbecoviruses.
Immune checkpoint B7-H3 is a therapeutic vulnerability in prostate cancer harboring PTEN and TP53 deficiencies
Authors: Wei Shi, Yin Wang, Yuehui Zhao, Justin Jimin Kim, Haoyan Li, Chenling Meng, Feiyu Chen, Jie Zhang, Duncan H. Mak, Vivien Van, Javier Leo, Brad St. Croix, Ana Aparicio, Di Zhao
Journal: Science Translational Medicine (2023)

Checkpoint immunotherapy has yielded meaningful responses across many cancers but has shown modest efficacy in advanced prostate cancer. B7 homolog 3 protein (B7-H3/CD276) is an immune checkpoint molecule and has emerged as a promising therapeutic target. However, much remains to be understood regarding B7-H3's role in cancer progression, predictive biomarkers for B7-H3-targeted therapy, and combinatorial strategies. Our multi-omics analyses identified B7-H3 as one of the most abundant immune checkpoints in prostate tumors containing PTEN and TP53 genetic inactivation. Here, we sought in vivo genetic evidence for, and mechanistic understanding of, the role of B7-H3 in PTEN/TP53-deficient prostate cancer. We found that loss of PTEN and TP53 induced B7-H3 expression by activating transcriptional factor Sp1. Prostate-specific deletion of Cd276 resulted in delayed tumor progression and reversed the suppression of tumor-infiltrating T cells and NK cells in Pten/Trp53 genetically engineered mouse models. Furthermore, we tested the efficacy of the B7-H3 inhibitor in preclinical models of castration-resistant prostate cancer (CRPC). We demonstrated that enriched regulatory T cells and elevated programmed cell death ligand 1 (PD-L1) in myeloid cells hinder the therapeutic efficacy of B7-H3 inhibition in prostate tumors. Last, we showed that B7-H3 inhibition combined with blockade of PD-L1 or cytotoxic T lymphocyte-associated protein 4 (CTLA-4) achieved durable antitumor effects and had curative potential in a PTEN/TP53-deficient CRPC model. Given that B7-H3-targeted therapies have been evaluated in early clinical trials, our studies provide insights into the potential of biomarker-driven combinatorial immunotherapy targeting B7-H3 in prostate cancer, among other malignancies.